EP0404283B1 - 11-Bêta-aryl-4-estrène, son procédé de préparation et son application comme médicament - Google Patents

11-Bêta-aryl-4-estrène, son procédé de préparation et son application comme médicament Download PDF

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EP0404283B1
EP0404283B1 EP90250142A EP90250142A EP0404283B1 EP 0404283 B1 EP0404283 B1 EP 0404283B1 EP 90250142 A EP90250142 A EP 90250142A EP 90250142 A EP90250142 A EP 90250142A EP 0404283 B1 EP0404283 B1 EP 0404283B1
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hydroxy
phenyl
group
oestren
compound
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EP0404283A2 (fr
EP0404283A3 (fr
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Arwed Dr. Cleve
Cornelius Dr. Scheidges
Günter Dr. Neef
Eckhard Dr. Ottow
Walter Dr. Elger
Sybille Dr. Beier
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0085—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0092—Alkenyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • the invention particularly relates to compounds in which X represents an oxygen atom.
  • the alkoxy, acyloxy, alkyl, acyl and hydroxyalkyl groups contained in R2, R3, R5 and Y of the general formula I should each contain 1 to 10 and the alkoxyalkyl or acyloxyalkyl groups in Y contain 2 to 10 carbon atoms.
  • the preferred groups of the alkoxy groups are the methoxy, ethoxy, propoxy and isopropoxy groups, the formyl (oxy), acetyl (oxy) and propionyl (oxy) groups come from the acyl (oxy) groups special meaning too.
  • the methyl, ethyl, propyl, isopropyl and tert-butyl group should be mentioned in particular, and of the hydroxyalkyl groups the corresponding radicals which are substituted in any position by a hydroxyl group are preferred.
  • Y can preferably also be a hydrogen, chlorine or bromine atom.
  • the alkoxy or acyloxy groups mentioned for R6, which can be both straight-chain and branched, are the methoxy, ethoxy, propoxy, isopropoxy and. the formyloxy, acetyloxy and propionyloxy group are particularly preferred.
  • C1-C8-alkyl and alkoxyalkyl radicals which can represent R4, these are primarily the methyl, ethyl, propyl, isopropyl, cyclopentyl and cyclohexyl radical or the alkoxymethyl or 1- or 2- Alkoxyethyl groups with said alkyl radicals; of the C1-C8 acyl radicals for R4 is particularly intended for the acetyl, propionyl and isobutylryl radical.
  • R4 stands for the amino group R7 and R8 preferably each represent a methyl radical, but the ethyl radical is also of particular importance, in which case either both radicals on the nitrogen atom represent an ethyl radical or one represents a methyl radical and one represents an ethyl radical.
  • R9 the methyl, ethyl and 2- (dimethylamino) ethyl group are particularly noteworthy.
  • the 3-thienyl, 3-furyl and 3-pyrrolyl radical are preferably with R1 mit in the meaning of a cyano, methoxy or dimethylamino group.
  • Suitable heteroaryl radicals of the formula I ⁇ are, in particular, the 3-or 4-pyridyl, the 5-pyrimidinyl, 4-pyridazinyl or pyrazinyl radical.
  • the phenyl radical of the formula I ⁇ has, in particular, the cyano, methoxy or dimethylamino group as the substituent R10, these substituents in turn preferably being in the p-position of the phenyl ring.
  • the compounds of the general formula I are competitive antagonists of progesterone (antigestagens).
  • antigestagens drugs which have become known until recently have a preferably substituted 11 ⁇ -phenyl radical (A. Belanger, D. Philibert and G. Teutsch, Steroids 37 , 2742 (1981); D. Philibert, T. Ojasoo and JP Raynand, Endocrinology 10 , 1850 (1977), EP-A 057 115; G. Teutsch, T. Ojasoo and JP Raynand, J. Steroid Biochem, 31, 549 (1988)).
  • Antigestagens of steroidal origin have also recently been found in which, instead of the 9,10 double bond, there is a methylene bridge between the 9 C atom and one of the ortho C atoms of the 11 ⁇ -aryl ring (EP-A 0283428).
  • the introduction of the 11 ⁇ -aryl radical causes the transition from gestagen to antigestagenic activity.
  • it has so far not been possible to produce an antigestagen closest to the progesterone so to speak "the antiprogesterone", which would not have a 9,10-double bond but would have a "free" 10 ⁇ -substituent, for example a hydrogen atom, in addition to an 11 ⁇ -aryl radical.
  • the isomerization is preferably heated to a temperature between 80 and 120 ° C. in an inert solvent such as toluene.
  • the reaction time is at least 45 minutes, but may be 24 hours or more if necessary.
  • Both mineral and organic acids are suitable as acids; of the latter, p-toluenesulfonic acid is preferred.
  • the compounds of the general formula Ia can already be an end compound of the general formula I if the substituents R4, A and B in the starting compound of the general formula II are those substituents which withstand the drastic reaction conditions required for the isomerization. In particular, free hydroxyl groups on a tertiary carbon atom are eliminated under these reaction conditions.
  • Process steps a), b), c) and d) are carried out according to methods known per se.
  • the oxidation a) of the hydroxy group to the keto group can be carried out, for example, according to Oppenauer or with chromic acid reagents (Jones' reagent) or chromic acid pyridine.
  • the protective group for the 3-keto function is preferably the ethane-1,2-diyl-bis (thio) group, which is obtained by reacting the 3-keto compound with ethane-1,2-dithiol in the presence of, for example, p-toluenesulfonic acid on the steroid. 3-C atom can be introduced.
  • reaction step c) serves to build up the substituent R4 or R 4 ' in the p-position on the 11 ⁇ -phenyl ring. This procedure is necessary if R4 represents such a substituent that does not withstand the drastic isomerization conditions, for example an allyl or vinyl radical.
  • the starting point for this structure is the 11 ⁇ - (4-hydroxyphenyl) compound, which can be obtained from the corresponding methoxy compound by ether cleavage, for example with sodium methanethiolate in a solvent such as dimethylformamide.
  • the 11 ⁇ -phenyl radical then has the desired or a precursor of the desired substitution.
  • suitable oxidizing agents eg hydrogen peroxide or peracids
  • dialkylamine compounds for example with diisobutylaluminum hydride in toluene to the N-formyl-N-alkylaminophenyl intermediates and then with lithium aluminum hydride
  • NHN-alkyl compounds for example with lithium aluminum hydride or with lithium in liquid ammonia
  • the latter are then, if desired, acylated in a manner known from the literature and, if appropriate, then subsequently reduced in a known manner to, for example, lithium aluminum hydride to give the new dialkylamine derivative (see DE 36 23 038).
  • the organometallic compound can also be formed in situ and reacted with the 17-ketone.
  • acetylene and an alkali metal especially potassium, sodium or lithium
  • the alkali metal can also act in the form of, for example, methyl or butyllithium.
  • Dialkyl ethers, tetrahydrofuran, dioxane, benzene and toluene are particularly suitable as solvents.
  • 3-hydroxypropin, propene or propane in the 17-position is carried out by reacting the 17-ketone with the dianion of the propargyl alcohol (3-hydroxypropine), for example the dipotassium salt of the propargyl alcohol generated in situ, for the 17 ⁇ - (3rd -Hydroxyprop-1-inyl) -17 ⁇ -hydroxy derivative or with metalated derivatives of 3-hydroxypropine, for example with 1-lithium-3- (tetrahydropyran-2'-yloxy) prop-1-in-1-id, for the 17th - [3- (Tetrahydropyran-2'-yloxy) prop-1-ynyl] -17 ⁇ -hydroxy derivative, which can then be hydrogenated to the 17- (3-hydroxypropyl or hydroxypropenyl) 17 ⁇ -hydroxy compounds.
  • 3-hydroxypropine for example the dipotassium salt of the propargyl alcohol generated in situ
  • metalated derivatives of 3-hydroxypropine for example with 1-lithium-3- (tetrahydro
  • This can be achieved, for example, by hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of noble metal catalysts such as platinum or palladium.
  • solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate
  • noble metal catalysts such as platinum or palladium.
  • Homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups are introduced in a corresponding manner with homologues of propargyl alcohol.
  • connection with the Z-configured double bond in the hydroxypropenyl group is formed by hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, JA Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, page 134; and HO House: Modern Synthetic Reactions 1972, page 19).
  • a deactivated noble metal catalyst for example, 10% palladium on barium sulfate are present an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate. The hydrogenation is stopped after the absorption of one equivalent of hydrogen.
  • connection with the E-configured double bond in the hydroxypropenyl group is formed by reducing the acetylenic triple bond in a manner known per se.
  • a whole series of methods for converting alkynes to trans-olefins are described in the literature, for example reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 (1941) 216), with sodium amide in liquid ammonia (J Chem. Soc. 1955, 3558), with lithium in low molecular weight amines (JA Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc.
  • the hydroxyalkenes can also be introduced directly by adding a corresponding metalated hydroxyalkenyl compound, such as, for example, 1-lithium-3- (tetrahydropyran-2'-yloxy) prop-1 (E) -en (J. Org. Chem. 40 2265 ) or 1Lithium-3- (tetrahydropyran-2'-yloxy) prop-1 (Z) -en (Synthesis 1981 , 999) homologs can also be introduced in this way.
  • a corresponding metalated hydroxyalkenyl compound such as, for example, 1-lithium-3- (tetrahydropyran-2'-yloxy) prop-1 (E) -en (J. Org. Chem. 40 2265 ) or 1Lithium-3- (tetrahydropyran-2'-yloxy) prop-1 (Z) -en (Synthesis 1981 , 999) homologs can also be introduced in this way.
  • 3-hydroxypropane in the 17-position can also be carried out directly by reacting the 17-ketone with metalated derivatives of 3-halopropanols - the hydroxyl group in the metalation step as an alcoholate (Tetrahedron Letters 1978 , 3013) or as a protected function (J. Org. Chem. 37 , 1947) is present - to the 17- (3-hydroxypropyl) -17 ⁇ -hydroxy compound or to the compound protected at the terminal hydroxyl group.
  • the protecting groups include, for example, the ethoxyethyl, tetrahydropyranyl and methoxymethyl groups.
  • the 17- (3-hydroxypropyl) or 17- (4-hydroxybutyl) compound is oxidized in a manner known per se, for example with Jones' reagent, manganese dioxide, pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or the Fetizon reagent silver carbonate / Celite (Compt. rend. 267 [1968] 900).
  • the 17-cyanomethyl side chain is built up in a manner known per se from the 17-ketone, for example via the 17-spiroepoxide and cleavage of the spiroepoxide with HCN according to Z. Chem. 18 (1978) 259-260.
  • the 17-hydroxyacetyl side chain is also introduced by methods known per se, for example according to the methods described in J. Org. Chem. 47 (1982), 2993-2995, Chem. Ber. 113 (1984), 1184 and U.S. Patent 4,600,538.
  • Free hydroxy groups can be alkylated or acylated in a manner known per se.
  • the introduction of the substituents R2 and R3 as described under d) can also be carried out first and then the substituent R4 can be built up according to c), depending on whether the process conditions of the second reaction step impair the substituents introduced first but built up.
  • the compounds of general formula I with X in the meaning of an oxygen atom can be obtained by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20 and + 40 ° C. in the oximes (formula I with X in the meaning of the hydroxyimino group N OH , where the hydroxyl group can be syn- or anti-stable).
  • Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU), with pyridine being preferred.
  • the new compounds of general formula I and their addition salts with pharmaceutically acceptable acids are valuable pharmaceuticals. They have a strong affinity for the gestagen receptor and have surprisingly strong antigestagenic, antiglucocorticoide, antimineralcorticoide and antiandrogenic properties. These important biological effects can be used for medical purposes. Active substances of this type with pronounced antigestagenic activity are suitable for triggering abortions because they displace the progesterone required for maintaining pregnancy from the receptor. They are therefore valuable and interesting with regard to their use for postcoital fertility control.
  • the new compounds can also be used to treat endometriosis. They can also be used against hormonal irregularities, for triggering menstruation and for induction of labor. They can also be used to treat hormone-dependent carcinomas.
  • the compounds of the general formula I according to the invention and their addition salts with pharmaceutically acceptable acids also have antiglucocorticoid activity and can therefore also be used as medicaments for the therapy of corticoid-induced disorders (glaucoma) and for combating side effects which occur during long-term treatment with glucocorticoids (Cushing Syndrome). They therefore also make it possible to combat the disorders attributable to supersecretion of the glucocorticoids, especially obesity, arteriosclerosis, hypertension, osteoporosis, diabetes and insomnia.
  • the compounds of general formula I according to the invention and their addition salts with pharmaceutically acceptable acids with antiandrogenic activity can be used in the treatment of hypertrophy and prostate cancer. They also enable specific therapy of androgenization symptoms in women: the pathological hairiness in hirsutism, androgenetic alopecia and the increased sebum gland function in acne and seborrhea can be influenced favorably.
  • the invention thus also relates to medicaments based on the compounds of the general formula I and their addition salts with pharmaceutically acceptable acids, if appropriate together with the customary auxiliaries and carriers.
  • the compounds according to the invention and their salts can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
  • the active ingredient (s) can be combined with the auxiliaries customary in galenics, such as gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as Tweens (R) or Myrj (R) , magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents. , Dispersants, emulsifiers, preservatives and flavorings for flavor correction (eg essential oils) can be mixed.
  • the invention thus also relates to pharmaceutical compositions which contain at least one compound according to the invention or one of its addition salts with pharmaceutically acceptable acids as the active ingredient.
  • hydrochlorides and the methanesulfonates are to be mentioned in particular as addition salts of the products according to the invention with acids.
  • One dose unit contains about 1-100 mg of active ingredient (s).
  • the dosage of the compounds according to the invention in humans is about 1-1000 mg per day.
  • the abortive effect was determined to identify the antigestagenic effect.
  • the animals were treated with the substance to be tested or the solvent after the blastocysts had been nidated by d5 p.c. to d7 p.c. To d9 p.c. the animals were sacrificed and the uteri examined for implants and absorption sites. Photos of all uteri were taken. The absence of implants, pathological, hemorrhagic or otherwise abnormal nidation sites was considered an abortion.
  • test substances were dissolved in a benzyl benzoate-castor oil mixture (ratio 1 + 4).
  • the vehicle volume per single dose was 0.2 ml.
  • the treatment was subcutaneous.
  • Example 2 shows the preparation of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] 10 ⁇ , 11 ⁇ - (5-methoxy-o-phenylene thio) -estran-5 ⁇ , 17 ⁇ -diol.
  • a nucleophilic reagent other than propyne in the analogous implementation of step 1L, compounds of the general formula II are obtained in which R 4 'represents a methoxy group.
  • reaction mixture is mixed with 15 ml of saturated NH4Cl solution and extracted with ethyl acetate, the organic phase washed with water and dried over Na2SO4, the solvent removed in vacuo.
  • Column chromatography gives 484 mg 1A as a foam.
  • connection 1I can also be established according to the following regulation:
  • Example 1A The procedure and processing are carried out as described in Example 1A. Amounts used: 12.73 g of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 ⁇ , 10 ⁇ -epoxy-estr-9 (11) -en-17 ⁇ -ol in 100 ml abs . Tetrahydrofuran, 22.3 g 2-bromo-5-methoxythiophenol in 182 ml abs. Tetrahydrofuran, 40 ml 2.5 molar butyllithium solution in n-hexane. Column chromatography gives 17.99 g 2A , m.p .: 117-119 ° C.
  • Example 1G Execution and processing are carried out as in Example 1G. Yield: 1.09 g 2B , mp: 95-97 ° C.
  • 225 mg 6B are produced from 327 mg 6A with 400 ⁇ l cyclohexanone and 409 mg aluminum triisopropylate in 10 ml toluene.
  • IR (KBr): 1740 cm ⁇ 1 (C O).
  • 207 mg 6C are prepared from 215 mg 6B with 2.1 ml of a 15% solution of butyllithium in hexane in 20 ml tetrahydrofuran saturated with propyne. Crystallization from pentane / ethyl acetate leads to 168 mg of the named compound.
  • 234 mg of 7H are prepared from 453 mg of 7G with 3.27 g of glyoxylic acid and 2.98 ml of 4 M aqueous hydrochloric acid in 8 ml of acetone and 8 ml of glacial acetic acid.
  • 576 mg of 12A are prepared from 863 mg of 7B with 3 ml of 4 M aqueous hydrochloric acid in 70 ml of acetone.
  • 347 mg 12D are produced from 390 mg 12C with 360 ⁇ l cyclohexanone and 70 mg aluminum triisopropylate in 15 ml toluene.
  • IR (KBr): 1740 cm ⁇ 1 (C O).
  • 99 mg 12E is prepared from 100 mg 12D with 800 ⁇ l of a 15% solution of butyllithium in hexane in 10 ml tetrahydrofuran saturated with propyne.
  • 34 mg of 12F are prepared from 89 mg of 12E with 64 mg of glyoxylic acid and 600 ⁇ l of 4 M aqueous hydrochloric acid in 2 ml of acetone and 2 ml of glacial acetic acid after crystallization from methylene chloride / hexane.
  • IR (KBr): 2240 cm ⁇ 1 (C ⁇ C), 1655 cm ⁇ 1 (C O).
  • 124 mg of 13B are prepared from 230 mg of 13A with 1.60 g of glyoxylic acid and 1.50 ml of 4 M aqueous hydrochloric acid in 5 ml of acetone and 5 ml of glacial acetic acid.
  • IR (KBr): 2230 cm ⁇ 1 (C ⁇ C), 1660 cm ⁇ 1 (C O).
  • a solution of 4.40 g of 4C in 300 ml of dioxane is stirred with 1.35 g of lithium chloride for 15 minutes at room temperature under a protective gas.
  • 8.3 ml of hexabutylditin and 735 mg of tetrakis (triphenylphosphine) palladium (0) are added.
  • the reaction mixture is heated to 100 ° C. for 90 minutes.
  • 2.3 g of 5-bromopyrimidine are added and the mixture is heated to boiling for a further 7 hours. After cooling, it is filtered through Celite, washed with ethyl acetate and concentrated in vacuo. After column chromatography, 2.37 g of 19A are obtained .

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Claims (9)

11β-aryl-4-estrènes de formule générale I
Figure imgb0062
 dans laquelle
X   représente un atome d'oxygène, le groupement hydroxyimino >N∼OH ou deux atomes d'hydrogène,
R¹   représente un atome d'hydrogène ou un groupe méthyle,
R²   représente un groupe hydroxy, alcoxy en C₁-C₁₀ ou acyloxy en C₁-C₁₀,
R³   représente un atome d'hydrogène, le groupement -(CH₂)nCH₂Z, dans lequel n est égal à 0, 1, 2, 3, 4 ou 5, Z est un atome d'hydrogène, le groupe cyano ou le reste -OR⁵ avec R⁵ = H, alkyle en C₁-C₁₀ ou acyle en C₁-C₁₀, le groupement -(CH₂)mC≡C-Y dans lequel m est égal à 0, 1 ou 2 et Y est un atome d'hydrogène, de fluor, de chlore, de brome ou d'iode ou un reste hydroxyalkyle en C₁-C₁₀, alcoxyalkyle en C₁-C₁₀ ou acyloxyalkyle en C₁-C₁₀, le groupement -(CH₂)p-CH=CH-(CH₂)kCH₂R⁶ dans lequel p est 0 ou 1 et k est 0, 1 ou 2 et R⁶ est un atome d'hydrogène, un groupe hydroxy ou un reste alcoxy en C₁-C₄ ou acyloxy en C₁-C₄,
ou bien R² et R³ forment ensemble un reste de formule
Figure imgb0063
 où x= 1 ou 2,
R⁴   représente un atome d'hydrogène, un groupe cyano, un atome de chlore, de fluor, de brome ou d'iode, un groupe trialkylsilyle, un groupe trialkylstannyle, un reste alkyle, acyle ou alcoxyalkyle en C₁-C₈ linéaire ou ramifié, saturé ou insaturé, un groupe amino
Figure imgb0064
 dans lequel R⁷ et R⁸ représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle en C₁-C₄, ou un oxyde d'amine correspondant
Figure imgb0065
 ou les groupements -OR⁹ ou -S(O)iR⁹ avec i = 0, 1 ou 2, dans lesquels R⁹ représente un atome d'hydrogène ou un groupe méthyle, éthyle, propyle, isopropyle, méthoxyphényle, allyle ou 2-diméthylaminoéthyle, ou un reste hétéroaryle de formule Iα
Figure imgb0066
 dans laquelle A représente un atome d'azote, d'oxygène ou de soufre, -B-D-E- représente la séquence d'éléments -C-C-C-, -N-C-C- ou -C-N-C- et R¹⁰ est un atome d'hydrogène, un groupe cyano, un atome de chlore, de brome, de fluor ou d'iode, un groupe trialkylsilyle, un groupe trialkylstannyle, un reste alkyle, acyle ou alcoxyalkyle en C₁-C₈ linéaire ou ramifié, saturé ou insaturé, un groupe amino
Figure imgb0067
 dans lequel R⁷ et R⁸ représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle en C₁-C₄, ou un oxyde d'amine correspondant
Figure imgb0068
 ou les groupements -OR⁹ ou -S(O)iR⁹ avec i = 0, 1 ou 2, dans lesquels R⁹ représente un atome d'hydrogène ou un groupe méthyle, éthyle, propyle, isopropyle, méthoxyphényle, allyle ou 2-diméthylaminoéthyle, ou un reste hétéroaryle de formule 1β
Figure imgb0069
 dans laquelle A est un atome d'azote et -B-D-E- représente la séquence d'éléments -C-C-C-, -N-C-C-, -C-N-C- ou -C-C-N- et R¹⁰ a la signification déjà indiquée,
ou un reste phényle de formule Iγ
Figure imgb0070
 dans laquelle R¹⁰ a la signification déjà indiquée,
et leurs sels d'addition d'acides pharmaceutiquement acceptables.
La 11β-[4-(diméthylamino)phényl]-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la 11β-(4-acétylphényl)-17β-hydroxy-4-estrène-3-one;
la 11β-(4-acétylphényl)-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la 11β-(4-acétylphényl)-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-(4-acétylphényl)-17β-hydroxy-17α-(3-hydroxy1Z-propényl)-4-estrène-3-one;
la 11β-[4-(diméthylamino)phényl]-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-[4-(3-furyl)phényl]-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la 11β-[4-(3-furyl)phényl]-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-[4-(5-pyrimidinyl)phényl]-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la 11β-[4-(5-pyrimidinyl)phényl]-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-[4-(3-pyridyl)phényl]-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one; la 11β-[4-(3-pyridyl)phényl]-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-[4-(4-cyanophényl)phényl]-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la 11β-[4-(4-cyanophényl)phényl]-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-(4-vinylphényl)-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-(4-vinylphényl)-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la 11β-[4-(1-hydroxyéthyl)phényl]-17β-hydroxy-17α-(3-hydroxy-1Z-propényl)-4-estrène-3-one;
la 11β-[4-(diméthylamino)phényl]-17β-hydroxy-17α-méthoxyméthyl-4-estrène-3-one;
la 11β-[4-(diméthylamino)phényl]-17β-hydroxy-17α-cyanométhyl-4-estrène-3-one;
la (11β,17β)-4',5'-dihydro-11-[4-(diméthylamino)phényl]spiro[estr-4-ène-17,2'(3'H)furane]-3-one;
la (11β,17β)-3',4'-dihydro-11-[4-(diméthylamino)phényl]spiro[estr-4-ène-17,2'(5'H)furane]-3,5'-dione;
la (11β,17β)-11-[4-(diméthylamino)phényl]spiro[estr-4-ène-17,2'(5'H)furane]-3-one;
le 11β-[4-(diméthylamino)phényl]-17α-(1-propynyl)-4-estrène-17β-ol;
le 17β-hydroxy-3-oxo-11β-[4-(3-pyridinyl)phényl]-4-estrène-17α-acétonitrile;
le (E)-17β-hydroxy-3-(hydroxyimino)-11β-[4-(3-pyridinyl)phényl]-4-estrène-17α-acétonitrile;
le (Z)-17β-hydroxy-3-(hydroxyimino)-11β-[4-(3-pyridinyl)phényl]-4-estrène-17α-acétonitrile;
la 17β-hydroxy-17α-(2-propényl)-11β-[4-(3-pyridinyl)phényl]-4-estrène-3-one;
la 17β-hydroxy-17α-(méthoxyméthyl)-11β-[4-(3-pyridinyl)phényl]-4-estrène-3-one;
la 11β-(4-éthylphényl)-17β-hydroxy-17α-(1-propynyl)-4-estrène-3-one;
la (Z)-11β-(4-éthylphényl)-17β-hydroxy-17α-(3-hydroxy-1-propényl)-4-estrène-3-one;
la (Z)-11β-[4-(2-furanyl)phényl]-17β-hydroxy-17α-(3-hydroxy-1-propényl)-4-estrène-3-one;
la 11β-(4-éthénylphényl)-17β-hydroxy-17α-méthyl-4-estrène-3-one;
la (Z)-17β-hydroxy-17α-(3-hydroxy-1-propényl)-11β-(4-méthylphényl)-4-estrène-3-one;
la (11β,17β)-11-[4-(5-pyrimidinyl)phényl]spiro[estr-4-ène-17,2'(3'H)furane]-3-one.
Procédé de préparation de 11β-aryl-4-estrènes de formule générale I
Figure imgb0071
 dans laquelle
X   représente un atome d'oxygène, le groupement hydroxyimino >N∼OH ou deux atomes d'hydrogène,
R¹   représente un atome d'hydrogène ou un groupe méthyle,
R²   représente un groupe hydroxy, alcoxy en C₁-C₁₀ ou acyloxy en C₁-C₁₀,
R³   représente un atome d'hydrogène, le groupement -(CH₂)nCH₂Z, dans lequel n est égal à 0, 1, 2, 3, 4 ou 5, Z est un atome d'hydrogène, le groupe cyano ou le reste -OR⁵ avec R⁵ = H, alkyle en C₁-C₁₀ ou acyle en C₁-C₁₀, le groupement -(CH₂)mC≡C-Y dans lequel m est égal à 0, 1 ou 2 et Y est un atome d'hydrogène, de fluor, de chlore, de brome ou d'iode ou un reste hydroxyalkyle en C₁-C₁₀, alcoxyalkyle en C₁-C₁₀ ou acyloxyalkyle en C₁-C₁₀, le groupement -(CH₂)p-CH=CH-(CH₂)kCH₂R⁶ dans lequel p est 0 ou 1 et k est 0, 1 ou 2 et R⁶ est un atome d'hydrogène, un groupe hydroxy ou un reste alcoxy en C₁-C₄ ou acyloxy en C₁-C₄,
ou bien R² et R³ forment ensemble un reste de formule
Figure imgb0072
 où x = 1 ou 2,
R⁴   représente un atome d'hydrogène, un groupe cyano, un atome de chlore, de fluor, de brome ou d'iode, un groupe trialkylsilyle, un groupe trialkylstannyle, un reste alkyle, acyle ou alcoxyalkyle en C₁-C₈ linéaire ou ramifié, saturé ou insaturé, un groupe amino
Figure imgb0073
 dans lequel R⁷ et R⁸ représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle en C₁-C₄, ou un oxyde d'amine correspondant
Figure imgb0074
 ou les groupements -OR⁹ ou -S(O)iR⁹ avec i = 0, 1 ou 2, dans lesquels R⁹ représente un atome d'hydrogène ou un groupe méthyle, éthyle, propyle, isopropyle, méthoxyphényle, allyle ou 2-diméthylaminoéthyle, ou un reste hétéroaryle de formule Iα
Figure imgb0075
 dans laquelle A représente un atome d'azote, d'oxygène ou de soufre, -B-D-E- représente la séquence d'éléments -C-C-C-, -N-C-C- ou -C-N-C- et R¹⁰ est un atome d'hydrogène, un groupe cyano, un atome de chlore, de brome, de fluor ou d'iode, un groupe trialkylsilyle, un groupe trialkylstannyle, un reste alkyle, acyle ou alcoxyalkyle en C₁-C₈ linéaire ou ramifié, saturé ou insaturé, un groupe amino
Figure imgb0076
 dans lequel R⁷ et R⁸ représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle en C₁-C₄, ou un oxyde d'amine correspondant
Figure imgb0077
 ou les groupements -OR⁹ ou -S(O)iR⁹ avec i = 0, 1 ou 2, dans lesquels R⁹ représente un atome d'hydrogène ou un groupe méthyle, éthyle, propyle, isopropyle, méthoxyphényle, allyle ou 2-diméthylaminoéthyle, ou un reste hétéroaryle de formule 1β
Figure imgb0078
 dans laquelle A est un atome d'azote et -B-D-E- représente la séquence d'éléments -C-C-C-, -N-C-C-, -C-N-C- ou -C-C-N- et R¹⁰ a la signification déjà indiquée,
ou un reste phényle de formule Iγ
Figure imgb0079
 dans laquelle R¹⁰ a la signification déjà indiquée,
   et de leurs sels d'addition d'acides pharmaceutiquement acceptables, caractérisé en ce que l'on transforme un composé de formule générale II
Figure imgb0080
 dans laquelle
R¹ et R⁴ ont la signification indiquée pour la formule I,
A est un groupe β-hydroxy ou le reste OR², et
B est un atome d'hydrogène en α, un reste R³ en α, ou
A et B représentent ensemble un atome d'hydrogène,
   par chauffage en présence d'un acide, en un composé de formule générale Ia
Figure imgb0081
 dans laquelle R¹, A et B ont la signification donnée pour la formule II et R4' a la même signification que R⁴ dans la formule I, à condition que R⁴ soit stable dans les conditions réactionnelles sévères indiquées, puis
a) dans le composé de formule générale (Ia) dans lequel A est un groupe hydroxy en β et B un atome d'hydrogène en α, on oxyde si désiré le groupe 17-hydroxy en groupe 17-céto, et
b) on transforme la fonction 3-céto en un dithiocétal, tous les autres groupes céto éventuellement présents étant aussi cétalisés, ou bien
   on effectue d'abord l'étape b) puis l'étape a), puis
c) dans le cas où R4' dans le composé 3-thiocétalisé est un groupe méthoxy ou un groupe hydroxy et où R⁴ ne doit pas être un groupe méthoxy ou hydroxy dans le composé final de formule générale I désiré,
   on transforme le composé hydroxy, éventuellement après avoir dissocié le groupe méthoxy, en le composé d'acide perfluoroalkylsulfonique correspondant dans lequel la partie alkyle est un reste alkyle en C₁-C₄, et, à partir de celui-ci, on prépare, en présence d'un catalyseur à base d'un métal de transition, un composé de formule générale III
Figure imgb0082
 dans laquelle Z est un groupe céto protégé sous forme d'un dithiocétal,
soit directement par réaction avec un composé de trialkylétain substitué de façon correspondante R4''-Sn(alkyl)₃ ou avec un composé de bore substitué de façon correspondante R4''-BL₂ (L = hydroxy ou alkyle) dans lesquels R4'' est identique au R⁴ de la formule générale I ou représente un précurseur tautomère de R⁴, et alkyle représente un reste alkyle en C₁-C₄, soit indirectement en passant par un composé substitué par un reste trialkylétain (alkyl = alkyle en C₁-C₄) en position 4 du reste phényle en 11β que l'on a obtenu par réaction du composé perfluoralkylsulfonate avec Sn₂alkyl₆, et en traitant ensuite le composé 11β-(4-trialkylstannyl)phényle avec un composé R4''-Y dans lequel R4'' est identique au R⁴ de la formule générale I ou représente un précurseur tautomère de R⁴ et Y est un groupe partant, de préférence un atome d'halogène et en particulier un atome de brome, et
d) ensuite, dans le cas où R² et R³ dans le composé final de formule générale I désiré ne doivent pas représenter respectivement un groupe hydroxy et un atome d'hydrogène, ou bien dans le cas où R² et R³ ne doivent pas représenter ensemble un atome d'oxygène d'un groupe céto, on introduit par des procédés connus en soi les substituants R² et R³ désirés sur l'atome de carbone 17 du squelette du stéroïde, ou bien
   on effectue d'abord l'étape d) puis l'étape c),
   on sépare les groupes protecteurs, si désiré on alkyle ou on acyle les groupes hydroxy libres, et si désiré on transforme avec du chlorhydrate d'hydroxylamine le groupe 3-céto en un groupe 3-hydroxyimino >N∼OH, ou on transforme le groupe 3-céto en le composé dihydro, et on prépare éventuellement un sel d'addition avec un acide pharmaceutiquement acceptable.
Procédé selon la revendication 4, caractérisé en ce que l'on chauffe à une température de 80-120°C.
Procédé selon la revendication 3 ou 4, caractérisé en ce que l'on chauffe en présence d'un acide minéral.
Procédé selon la revendication 3 ou 4, caractérisé en ce que l'on chauffe en présence d'un acide organique.
Procédé selon la revendication 6, caractérisé en ce que l'on chauffe en présence de l'acide p-toluènesulfonique.
Compositions pharmaceutiques, caractérisées en ce qu'elles contiennent au moins un composé selon les revendications 1 ou 2, et un support pharmaceutiquement acceptable.
Utilisation des composés selon les revendications 1 ou 2 pour la préparation de médicaments.
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AU640664B2 (en) 1993-09-02
CN1048219A (zh) 1991-01-02
NO902800L (no) 1990-12-27
HUT54705A (en) 1991-03-28
HU209949B (en) 1994-12-28
EP0404283A3 (fr) 1991-07-31
FI903153A0 (fi) 1990-06-21
DE59010312D1 (de) 1996-06-13
GR3020098T3 (en) 1996-08-31
IE902280L (en) 1990-12-23
US5843933A (en) 1998-12-01
NO178768B (no) 1996-02-19
IL94819A (en) 1995-03-30
CN1061052C (zh) 2001-01-24
US5728689A (en) 1998-03-17
NO178768C (no) 1996-05-29
IE902280A1 (en) 1991-01-16
DK0404283T3 (da) 1996-09-09
CA2019404A1 (fr) 1990-12-23
CN1133296A (zh) 1996-10-16
NO902800D0 (no) 1990-06-22
ES2088959T3 (es) 1996-10-01
PT94462A (pt) 1991-02-08

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